2024
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke L, Strober J, Suh R, Paolella L, Li X, Rogers J, Petersen M, Nasiri A, Casals G, Kahn M, Cline G, Samuel V, Shulman G, Vatner D. High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis. IScience 2024, 27: 111175. PMID: 39524330, PMCID: PMC11550620, DOI: 10.1016/j.isci.2024.111175.Peer-Reviewed Original ResearchDuration of high-fat dietAttenuated insulin signalingHigh-fat dietHepatic insulin resistanceInsulin signalingInsulin stimulationLipogenic substrateStimulation of de novo lipogenesisReduced lipogenesisHFD feedingReduce DNLInsulin resistanceResistance per seLipogenesisInsulin resistance per sePathway selectionGlucose metabolismHepatic IRMiceFat dietSREBP1cINSRCeramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibition1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway
ZHENG J, NASIRI A, GASPAR R, HUBBARD B, SAKUMA I, MA X, MURRAY S, PERELIS M, BARNES W, SAMUEL V, PETERSEN K, SHULMAN G. 1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway. Diabetes 2024, 73 DOI: 10.2337/db24-1577-p.Peer-Reviewed Original ResearchReceptor kinase pathwaysMitochondrial fat oxidationHepatic insulin resistanceKinase pathwayExpression of cidebAmeliorated HFD-induced hepatic steatosisHFD-induced hepatic steatosisHFD-induced insulin resistanceSteatotic liver diseasePathogenesis of type 2 diabetesHepatic steatosisCidebHyperinsulinemic-euglycemic clamp studiesHepatic triglyceride accumulationInsulin resistanceReverse hepatic steatosisTriglyceride accumulationHepatic insulin sensitivityInsulin sensitivityPathwayHepatic expressionHigh-fatWhole-body insulin sensitivityLiver diseaseTranslocation
2020
A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCϵDAG contentMembraneFractionation methodKinaseMitochondriaNon‐alcoholic Fatty Liver Disease and Insulin Resistance
Petersen M, Samuel V, Petersen K, Shulman G. Non‐alcoholic Fatty Liver Disease and Insulin Resistance. 2020, 455-471. DOI: 10.1002/9781119436812.ch37.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseHepatic insulin resistanceFatty liver diseaseInsulin resistanceLiver diseaseDevelopment of NAFLDLipid-induced muscle insulin resistanceRandle glucose-fatty acid cycleCommon chronic liver diseaseType 2 diabetes mellitusHyperinsulinemic-euglycemic clamp studiesGlucose-fatty acid cycleLiver-related deathSkeletal muscleChronic liver diseaseNon-alcoholic steatohepatitisMajor risk factorLipid-induced hepatic insulin resistanceMuscle insulin resistanceDiabetes mellitusRisk factorsClamp studiesLipoprotein lipaseDiseaseProtein kinase C
2019
Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action
Abulizi A, Camporez JP, Jurczak MJ, Høyer KF, Zhang D, Cline GW, Samuel VT, Shulman GI, Vatner DF. Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action. The FASEB Journal 2019, 33: 8174-8185. PMID: 30922125, PMCID: PMC6593882, DOI: 10.1096/fj.201802706r.Peer-Reviewed Original ResearchConceptsWhole-body metabolismHepatic insulin actionHepatic insulin resistanceGlucocorticoid actionHepatic steatosisHepatic glycogen synthesisInsulin resistanceAdipose lipolysisFood intakeInsulin actionAdipose triglyceride lipase expressionGlucose-dependent organsReceptor knockout miceOral glucose challengeHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic conditionsGlycogen synthesisProtein kinase B phosphorylationInsulin responseGlucose challengeHepatic insulin responseHepatic insulinMetabolic cagesSteatosis
2018
Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice
Abulizi A, Camporez JP, Zhang D, Samuel VT, Shulman GI, Vatner DF. Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice. Metabolism 2018, 93: 1-9. PMID: 30576689, PMCID: PMC6401251, DOI: 10.1016/j.metabol.2018.12.003.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceEctopic lipid depositionInsulin resistanceHepatic lipid contentGlucocorticoid actionTransgenic miceLipid depositionSevere hepatic insulin resistanceTissue-specific insulin actionHepatic triglyceride contentHigh-fat dietHyperinsulinemic-euglycemic clampGlucocorticoid excessAkt serine phosphorylationGlucocorticoid activityHepatic steatosisFat dietLittermate controlsHepatic insulinInsulin actionTriglyceride contentPKCε activationDevelopment of lipidLipid contentMicePEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityPKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling
Gassaway BM, Petersen MC, Surovtseva YV, Barber KW, Sheetz JB, Aerni HR, Merkel JS, Samuel VT, Shulman GI, Rinehart J. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e8996-e9005. PMID: 30181290, PMCID: PMC6156646, DOI: 10.1073/pnas.1804379115.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedDiabetes Mellitus, Type 2Diet, High-FatDisease Models, AnimalGene Knockdown TechniquesHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverPhosphorylationProtein Kinase C-epsilonProteomicsRatsReceptor, InsulinRibosomal Protein S6Ribosomal Protein S6 Kinases, 70-kDaRNA, Small InterferingSignal TransductionConceptsHigh-fat diet-induced hepatic insulin resistanceDiet-induced hepatic insulin resistanceLipid-induced insulin resistanceProtein phosphorylationSiRNA-based screenProtein kinase C εSet of proteinsCross talkHepatic insulin resistanceQuantitative phosphoproteomicsMotif analysisUnknown regulatorKinase assaysPhosphoproteomic dataCanonical insulinP70S6KInsulin receptorImpact of lipidSystem-level approachPKCεDiacylglycerolPhosphorylationKey mediatorNew therapeutic approachesInsulin resistanceMembrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
LYU K, ZHANG D, NOZAKI Y, ZHANG Y, BHANOT S, CLINE G, SAMUEL V, SHULMAN G. Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo. Diabetes 2018, 67 DOI: 10.2337/db18-243-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceLipid-induced hepatic insulin resistanceDiglyceride acyltransferase 2Hepatic DAG contentInsulin resistanceHepatic insulin sensitivityInsulin sensitivityImpaired insulin-mediated suppressionActivation/translocationDGAT2 inhibitionAntisense oligonucleotideRegular chow dietInsulin-mediated suppressionHepatic insulin actionHepatic glucose productionInsulin receptor kinaseDAG contentChow dietASO treatmentIonis PharmaceuticalsInsulin actionGlucose productionPKCε activationSREBP-1cGilead SciencesAngptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents
Vatner DF, Goedeke L, Camporez JG, Lyu K, Nasiri AR, Zhang D, Bhanot S, Murray SF, Still CD, Gerhard GS, Shulman GI, Samuel VT. Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 2018, 61: 1435-1446. PMID: 29497783, PMCID: PMC5940564, DOI: 10.1007/s00125-018-4579-1.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAngiopoietin-Like Protein 8Angiopoietin-like ProteinsAnimalsBody CompositionCalorimetry, IndirectDiet, High-FatGlucose Tolerance TestInsulin ResistanceLipid MetabolismMaleMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseOligonucleotides, AntisensePeptide HormonesRatsRats, Sprague-DawleyConceptsHepatic insulin resistanceAdipose tissue lipoprotein lipaseInsulin resistanceEctopic lipid accumulationTissue lipoprotein lipaseAdipose tissueLipid uptakeTolerance testFed miceNon-alcoholic fatty liver diseaseAntisense oligonucleotideMixed meal tolerance testLipoprotein lipaseLipid accumulationDiet-induced NAFLDBariatric surgery patientsFatty liver diseaseHyperinsulinaemic euglycaemic clampMeal tolerance testSecond-generation antisense oligonucleotideAmeliorate insulin resistanceType 2 diabetesLipid-induced hepatic insulin resistanceLipoprotein lipase inhibitorWhite adipose tissue
2017
Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metabolism 2017, 27: 22-41. PMID: 28867301, PMCID: PMC5762395, DOI: 10.1016/j.cmet.2017.08.002.Peer-Reviewed Original ResearchConceptsInsulin resistanceNonalcoholic fatty liver diseaseFatty liver diseasePeripheral insulin resistanceHepatic insulin resistanceNew pharmacological strategiesHepatic complicationsBariatric surgeryLiver diseaseInsulin-stimulated glycogen synthesisHepatic diseasePharmacological strategiesNAFLDReceptor activationHepatic glucoseLipid metabolismInsulin receptor activationWeight lossEnergy expenditureHepatic diacylglycerolsGlycogen synthesisDiseaseLipid synthesisFlux of substratesComplicationsHepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans
Horst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisObese subjectsPKCε activationTissue-specific insulin sensitivityHepatic ceramide contentPeripheral insulin resistanceHepatic lipid accumulationPathogenesis of NAFLDLiver biopsyIntrahepatic triglyceridesLiver fatInsulin sensitivityAdipose tissueTranslational evidenceSteatosisLipid accumulationCeramide contentPKCε translocationSubjectsMolecular mechanismsDiacylglycerol contentHumansActivation
2016
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance
Petersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abulizi A, Zhang XM, Philbrick W, Hubbard SR, Jurczak MJ, Samuel VT, Rinehart J, Shulman GI. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. Journal Of Clinical Investigation 2016, 126: 4361-4371. PMID: 27760050, PMCID: PMC5096902, DOI: 10.1172/jci86013.Peer-Reviewed Original ResearchConceptsInsulin receptorKinase activityHigh-fat diet-induced hepatic insulin resistanceKinase activation loopNonalcoholic fatty liver diseaseLipid-induced hepatic insulin resistanceProtein kinase CHepatic insulin resistanceDiet-induced hepatic insulin resistanceDiacylglycerol-mediated activationActivation loopPKCε inhibitionAlanine mutationsInsulin resistanceMolecular mechanismsKinase CCritical pathophysiological rolePathogenesis of T2DMechanistic linkMutantsGlycogen synthesisConsequent inhibitionPhosphorylationActive configurationPKCεThe Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis
Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends In Endocrinology And Metabolism 2016, 27: 719-730. PMID: 27387598, PMCID: PMC5035631, DOI: 10.1016/j.tem.2016.06.005.Peer-Reviewed Original ResearchConceptsFructose consumptionHepatic fructose metabolismHepatic insulin resistanceImpairment of insulinDe novo lipogenesisHepatic steatosisInsulin resistanceEpidemiological studiesNovo lipogenesisMetabolic diseasesFructose metabolismLipogenic enzymesLipogenesisFatty acid synthesisKey transcription factorDiseaseAldolase BLipid synthesisAdditional mechanismHypertriglyceridemiaSteatosisTranscription factorsTherapyInsulinImpairment
2013
Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
Kumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, Fat I, Guigni B, Jurczak MJ, Birkenfeld AL, Kahn M, Perler BK, Puchowicz MA, Manchem VP, Bhanot S, Still CD, Gerhard GS, Petersen KF, Cline GW, Shulman GI, Samuel VT. Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance. Diabetes 2013, 62: 2183-2194. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.Peer-Reviewed Original ResearchConceptsPyruvate carboxylaseAntisense oligonucleotideHepatocyte fatty acid oxidationInsulin resistanceNonalcoholic fatty liver diseaseZucker diabetic fatty ratsHigh fat-fed ratsFatty liver diseaseLiver biopsy specimensDiabetic fatty ratsPlasma lipid concentrationsType 2 diabetesHepatic insulin sensitivityHuman liver biopsy specimensEndogenous glucose productionHepatic insulin resistancePlasma glucose concentrationPotential therapeutic approachSpecific antisense oligonucleotideFat-fed ratsCarboxylaseFatty acid oxidationDe novo fatty acid synthesisLiver diseaseTissue-specific inhibitionThyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways
Vatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, Grover GJ, Webb P, Phillips KJ, Weiss RE, Bogan JS, Baxter J, Shulman GI, Samuel VT. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. AJP Endocrinology And Metabolism 2013, 305: e89-e100. PMID: 23651850, PMCID: PMC3725564, DOI: 10.1152/ajpendo.00573.2012.Peer-Reviewed Original ResearchMeSH KeywordsAcetatesAnilidesAnimalsDietary FatsFatty LiverGene ExpressionGluconeogenesisGlucose Transporter Type 4HyperglycemiaHyperinsulinismInsulin ResistanceMaleMuscle, SkeletalNon-alcoholic Fatty Liver DiseasePhenolsRatsRats, Sprague-DawleySignal TransductionThyroid Hormone Receptors betaTriglyceridesConceptsEndogenous glucose productionHepatic insulin sensitivityInsulin sensitivityHepatic steatosisFat-fed ratsInsulin-stimulated peripheral glucose disposalTRβ agonistsInsulin-stimulated skeletal muscle glucose uptakePotent lipid-lowering drugsNonalcoholic fatty liver diseaseWhite adipose tissue lipolysisMale Sprague-Dawley ratsSkeletal muscle glucose uptakeGC-1 treatmentPeripheral glucose disposalFatty liver diseaseImpairs insulin sensitivityLipid-lowering drugsHepatic triglyceride contentAdipose tissue lipolysisMuscle glucose uptakeSprague-Dawley ratsHepatic insulin resistanceSkeletal muscle insulinPotential adverse effects
2011
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16381-16385. PMID: 21930939, PMCID: PMC3182681, DOI: 10.1073/pnas.1113359108.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic DAG contentInsulin resistanceHepatic insulin resistanceLiver diseaseHepatic steatosisCellular mechanismsHomeostatic model assessmentInsulin resistance indexMarkers of inflammationType 2 diabetesER stress markersLipid dropletsHepatic diacylglycerol contentEndoplasmic reticulum stressActivation of PKCεLiver biopsyNondiabetic individualsHepatocellular lipidsInsulin sensitivityCytoplasmic lipid dropletsDAG contentResistance indexAnimal models
2009
Insulin Resistance
Samuel V, Petersen K, Shulman G. Insulin Resistance. 2009, 469-483. DOI: 10.1002/9780470747919.ch31.Peer-Reviewed Original Research
2007
Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease
Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. Journal Of Clinical Investigation 2007, 117: 739-745. PMID: 17318260, PMCID: PMC1797607, DOI: 10.1172/jci30400.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceNonalcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceHigh-fat feedingLiver diseaseFat-induced hepatic insulin resistanceType 2 diabetes mellitusType 2 diabetesHepatic fat accumulationNovel therapeutic targetInsulin receptor kinase activityDiabetes mellitusHepatic steatosisFat accumulationRats resultsTherapeutic targetHepatic insulinReceptor kinase activityProtein kinase CεInsulin receptorCausal roleIsoforms of PKCAntisense oligonucleotideRats